Process for the asymmetric hydrogenation of a substituted acrylic acid or ester thereof

Abstract

Optically active diphosphines of the formula, ##STR1## in which the phosphinomethyl groups are trans to each other, form rhodium complexes useful as catalysts in hydrogenating substituted acrylic acids and their esters to optically active propionic acid derivatives.

Description

The examples which follow illustrate the invention.

EXAMPLE 1

A solution consisting of 0.032 mol (13.6 g) of the stereoisomer of trans-bis-(1,2-hydroxymethyl)-cyclobutane ditosylate having an optical rotation (.alpha.).sub.D = +60.4.degree. and 10 cm.sup.3 of tetrahydrofuran is run into a solution consisting of 0.065 mol (13.5 g) of sodium diphenylphosphide and 200 cm.sup.3 of a 1 : 1 mixture of dioxane and tetrahydrofuran. After heating under reflux, a precipitate is obtained which is filtered off and washed with benzene. The filtrate is evaporated to dryness and the diphosphine obtained is then recrystallised from absolute ethyl alcohol. Its microanalysis and IR and NMR spectrography are in agreement with the formula: ##STR5## (.alpha.).sub.D.sup.20 = -18.5.degree. (C = 1% in benzene), melting point = 107.degree. C.

The stereoisomer of trans-bis-(1,2-hydroxymethyl)-cyclobutane was produced by reduction, with lithium aluminium hydride, of (-)-trans-cyclobutanedicarboxylic acid of optical rotation (.alpha.).sub.D = -155.degree..

EXAMPLE 2

Starting from (+)-trans-cyclobutane-1,2-dicarboxylic acid and following the procedure of Example 1, the diphosphine of opposite optical rotation is obtained in substantially identical yield.

EXAMPLE 3

By replacing the sodium diphenylphosphide in the procedure of Example 1 by an identical molar amount of sodium dinaphthylphosphide, the following diphosphine is obtained: ##STR6## in a yield of 15%, (.alpha.).sub.D.sup.22 = 19.degree. (C = 0.7% in benzene).

EXAMPLE 4

By replacing the sodium diphenylphosphide in the procedure of Example 1 by an identical molar amount of sodium ditolylphosphide, the following diphosphine is obtained: ##STR7## in a yield of 36%, (.alpha.).sub.D.sup.22 = 14.5.degree. (C = 0.7% in benzene).

EXAMPLE 5

The diphosphine prepared in Example 1 is used in the hydrogenation of .alpha.-acetamidocinnamic acid.

The catalyst is prepared by adding, under argon, 0.05 mM of the diphosphine prepared as in Example 1 dissolved in 4 cm.sup.3 of benzene to a solution of 0.025 mM of the complex of the formula (RhCl-1,5-hexadiene).sub.2 in 6 cm.sup.3 of ethyl alcohol, and stirring the solution for 1 hour. 2.5 mM of .alpha.-acetamidocinnamic acid dissolved in 11 cm.sup.3 of ethyl alcohol and 4.5 cm.sup.3 of benzene are then added, the argon is replaced by hydrogen and hydrogenation is started.

The hydrogenation is complete after 1/2 hour at 25.degree. C. under a hydrogen pressure of 1 bar. The solution obtained is evaporated to dryness, the residue is taken up in a dilute solution of sodium hydroxide, and the insoluble catalyst is filtered off. The filtrate is acidified and extracted with ethyl acetate. Acetylated phenylalanine is thus obtained in 95% yield and with an (.alpha.).sub.D.sup.22 of 36.3.degree..

The optical yield is 70% based on the value (.alpha.).sub.D.sup.22 = 51.8(ethyl alcohol) for the optically pure product.

EXAMPLE 6

The process of Example 5 is repeated using .alpha.-acetamido-.beta.-p-hydroxyphenylacrylic acid as the substrate. The hydrogenation is complete after 1/2 hour at 25.degree. C under a hydrogen pressure of 1 kg/cm.sup.2. The solution is evaporated to dryness, the residue is then taken up in water, and the insoluble catalyst is filtered off. After evaporating the filtrate to dryness, acetylated tyrosine with an optical rotation of 41.5.degree. (water) is obtained in 92% yield. The optical yield is 86%.

EXAMPLE 7

The process of Example 5 is added, 0.15 mM of triethylamine being added to the reaction mixture at the same time as the substrate. Acetylated phenylalanine is obtained, after a treatment identical to that of Example 5, in 94% yield and with an (.alpha.).sub.D.sup.22 = 42.4.degree.. The optical yield is 82%.

EXAMPLES 8, 9, 10, 11, 12 and 13

Various substrates are hydrogenated under the working conditions of Example 7 using the rhodium complex prepared as in Example 5 as catalyst. For comparison, the following Table gives the optical yields obtained using, as the rhodium ligand, the following diphosphine, which is described in French Pat. No. 2,116,905: ##STR8##

TABLE __________________________________________________________________________ Optical yield % obtained using the di- Configuration Optical yield phosphine com- of the optical % obtaned plex of French isomer present with the cata- Patent No. Examples Substrate in excess lyst of Ex. 5 2116905 __________________________________________________________________________ R 87 80 9 R##STR9## 89 79 10 R##STR10## 76 63 11 R##STR11## 89 76 12 R##STR12## 90 67 13 R##STR13## 70 65 __________________________________________________________________________

The optical yields are calculated using the following optical rotations for the optically pure products:

N-acetyl-D-tyrosine (.alpha.).sub.D = -48.3.degree. (water)

N-acetyl-L-(4-hydroxy-3-methoxy-phenyl)-alanine (.alpha.).sub.D = +42.degree. (methyl alcohol)

N-benzoyl-L-(4-hydroxy-3-methoxy-phenyl)-alanine (.alpha.).sub.D = -32.7.degree. (methyl alcohol)

N-acetyl-D-(3,4-methylenedioxy-phenyl)-alanine (.alpha.).sub.D = -53.4.degree. (ethyl alcohol)

N-acetyl-L-tryptophane (.alpha.).sub.D = +25.degree. (95% ethyl alcohol)

N-benzoyl-L-tryptophane (.alpha.).sub.D = -10.4.degree. (ethyl alcohol)

The complexes containing the diphosphines of the invention as ligands make it possible to obtain higher optical yields than those obtained from the diphosphine described in French Pat. No. 2,116,905.

EXAMPLE 14

The phenylalanine of the opposite configuration to that obtained in Example 7 is obtained under the conditions of Example 7, by using as the diphosphine that obtained in Example 2. The optical yield is 81%.

EXAMPLE 15

3.1 mg of the complex of the formula [RhCl-1,5-cyclooctadiene].sub.2, 57 mg of the diphosphine of Example 1 and 400 cm.sup.3 of ethyl alcohol are introduced under an argon atmosphere into a reactor. The mixture is stirred for 1 hour. 66.62 g of .alpha.-acetamidocinnamic acid and 25 microlitres of triethylamine are then added and hydrogen is introduced under a pressure of 1 bar at 25.degree. C. After 4 hours 30 minutes the hydrogenation is complete. After treatment to remove the catalyst similar to that of Example 5, N-acetylphenylalanine is obtained, after extraction, in 97% chemical yield and with an optical rotation [.alpha.].sub.D.sup.22 of 42.5.degree. (optical yield 82%).

Claims

1. A process for the asymmetric hydrogenation of a substituted acrylic acid or ester thereof, which comprises hydrogenating a mixture of the said acid or ester and a rhodium complex in which the rhodium is bound to halogen and a diphosphine of the formula: ##STR14## in which the phosphinomethyl groups are in the trans-position relative to one another, and the radicals R.sub.1, R.sub.2, R'.sub.1 and R'.sub.2, which may be identical or different, each represent straight or branched alkyl of 1 to 8 carbon atoms, cycloalkyl of 5 or 6 ring carbon atoms, or aryl consisting of one or more benzene rings which are bonded to one another by a valency bond or which form with one another an ortho- or peri-condensed system, the said aryl being unsubstituted or substituted by straight or branched alkyl of 1 to 4 carbon atoms.

2. Process according to claim 1 in which the substituted acrylic acid or ester thereof which is hydrogenated is a derivative of acrylic acid or an ester thereof in which one of the hydrogen atoms carried by the ethylenic carbon atoms is replaced by a primary or secondary amino or acylamino group and a second hydrogen atom carried by the ethylenic carbon atoms may be replaced by straight or branched alkyl, cycloalkyl, an unsubstituted or substituted aromatic hydrocarbon group, or a heterocyclic group containing one or more oxygen, sulphur, or nitrogen atoms, and no other hydrogen atoms carried by the ethylenic carbon atoms are replaced.

3. Process according to claim 2 in which the compound hydrogenated has the formula: ##STR15## where R.sup.1 is alkyl of 1 to 4 carbon atoms, cyclopentyl, cyclohexyl, phenyl, phenyl substituted in the 3- and/or 4- positions by hydroxy, methoxy, ethoxy, or methylenedioxy, naphthyl, or 3-indolyl, R.sup.2 is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl, and R.sup.3 is hydrogen or alkyl of 1 to 4 carbon atoms.